Generation of protective immunity against Orientia tsutsugamushi infection by immunization with a zinc oxide nanoparticle combined with ScaA antigen

Na‑Young Ha1,2, Hyun Mu Shin1,2,3, Prashant Sharma1,2, Hyun Ah Cho4 , Chan‑Ki Min1,2, Hong‑il Kim1,2, Nguyen Thi Hai Yen1,2, Jae‑Seung Kang5 , Ik‑Sang Kim1,3, Myung‑Sik Choi1,3, Young Keun Kim4* and Nam‑Hyuk Cho1,2,3

Abstract Background: Zinc oxide nanoparticle (ZNP) has been applied in various biomedical fields. Here, we investigated the usage of ZNP as an antigen carrier for vaccine development by combining a high affinity peptide to ZNP. Results: A novel zinc oxide-binding peptide (ZBP), FPYPGGDA, with high affinity to ZNP (Ka = 2.26 × 106 M−1 ) was isolated from a random peptide library and fused with a bacterial antigen, ScaA of Orientia tsutsugamushi, the causa‑ tive agent of scrub typhus. The ZNP/ZBP-ScaA complex was efficiently phagocytosed by a dendritic cell line, DC2.4, in vitro and significantly enhanced anti-ScaA antibody responses in vivo compared to control groups. In addition, immunization with the ZNP/ZBP-ScaA complex promoted the generation of IFN-γ-secreting T cells in an antigendependent manner. Finally, we observed that ZNP/ZBP-ScaA immunization provided protective immunity against lethal challenge of O. tsutsugamushi, indicating that ZNP can be used as a potent adjuvant when complexed with ZBP-conjugated antigen. Conclusions: ZNPs possess good adjuvant potential as a vaccine carrier when combined with an antigen having a high affinity to ZNP. When complexed with ZBP-ScaA antigen, ZNPs could induce strong antibody responses as well as protective immunity against lethal challenges of O. tsutsugamushi. Therefore, application of ZNPs combined with a specific soluble antigen could be a promising strategy as a novel vaccine carrier system. Keywords: Zinc oxide nanoparticle, ZnO binding peptide, Scrub typhus, Vaccine

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